Intranasal and transdermal administration of kappa-opioid-receptor agonists: salvinorin a for the treatment of neuropsychiatric and addictive disorders

ABSTRACT

Methods of treating neuropsychiatric disorders including affective disorders and addiction involve intranasal or transdermal administration of a substantially selective kappa-opioid-receptor agonist that is also a partial D2 agonist, such as the compound salvinorin A. Also disclosed are intranasal, transdermal and/or inhalation systems for delivering the kappa-opioid-receptor agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation application of application Ser. No. 15/354,078,filed Nov. 17, 2016, which claims the benefit of U.S. ProvisionalApplication No. 62/256,409, filed Nov. 17, 2015, both of which areincorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION (1) Field of the Invention

The present invention is related to the treatment of neuropsychiatricconditions with kappa-opioid-receptor agonists and, in particular, tointranasal, transdermal and inhalation systems and methods ofadministration of kappa-opioid-receptor agonists for the treatment ofneuropsychiatric conditions.

(2) Description of the Related Art

Salvinorin A is a naturally occurring psychoactive compound isolatedfrom Salvia divinorum. Studies have demonstrated that salvinorin A is auniquely selective kappa-opioid-receptor agonist with no significanteffect on a battery of 50 other receptors, transporters and ion channelsincluding mu- and delta-opioid receptors (Roth et al., 2004). Inaddition to having kappa-opioid-agonist activity, salvinorin A has beenfound to be a D2 receptor partial agonist (Seeman et al., 2009).Notably, salvinorin A has been shown to have no significant effect on5HTP_(2A) receptors and as a result, administration of salvinorin A to asubject would not be expected to produce mania (Yatham et al., 2010).Recent studies have suggested that salvinorin A may have anti-depressionand anti-addiction properties among other potentially beneficialproperties (Morani et al., 2009; Prevatt-Smith et al, 2011; Harden etal., 2012; Orton et al., 2014).

Several routes of administration have been used for Salvia divinorum andfor salvinorin A with varying degrees of success. In traditionalpractice among the Mazatec people of Mexico, Salvia divinorum wasingested by chewing the fresh leaves as a quid or by smoking (Valdes,1994; Siebert, 1994). Absorption upon chewing is apparently by thebuccal route in as much as encapsulated salvinorin A is inactive whenadministered orally (Siebert, 1994; Ott, 1995). Sublingualadministration has generally yielded inconsistent results or noabsorption at all (Siebert, 1994; Mendelson et al., 2011). The mostcommon route of administration of Salvia divinorum has been inhalationby smoking the leaves (Giroud et al., 2000). More recently, theinhalation route of administration has been used for the activecomponent, salvinorin A, in human subjects (Johnson et al., 2011;Maqueda et al., 2015).

Although infrequently used, the intranasal route of administration hasbeen proposed for use in pharmacologic treatment of neuropsychiatricconditions. Potential advantages of intranasal administration are rapidonset of action, the ability to bypass the blood-brain barrier,improvement in bioavailability and avoidance of parenteraladministration (Andrade, 2015). Nevertheless, there are numerouschallenges and potential problems that have limited the use ofintranasal administration of drugs for the treatment of neuropsychiatricconditions (Dhuria, 2010; Djupesland, 2014). In spite of this, theneuropsychiatric drug ketamine is currently under experimentalinvestigation using the intranasal route of administration for treatmentof acute and chronic pain, autism, depression and other conditions(Afridi, 2013; Yeaman, 2014; Clark, 2014, Lapidus, 2014; Graudins,2015). Naltrexone can potentiate the effects of ketamine (Krystal etal., 2006).

Similar to the intranasal route of administration, transdermaladministration presents challenges and only a few medications can bedelivered through the transdermal route in therapeutic amounts (Paudel,2010; Ita, 2015).

As noted above, numerous studies have evaluated different routes ofadministration for salvinorin A. Nevertheless, none of the routes ofadministration that have been studied are particularly suited for use inneuropsychiatry.

BRIEF SUMMARY OF THE INVENTION

Accordingly, the applicant herein has invented an intranasal system andmethod and a transdermal system and method for administration ofkappa-opioid-selective agonists such as salvinorin A, for the treatmentof neuropsychiatric conditions.

Thus in various embodiments, the present invention involves a method oftreating an affective disorder in a patient in need thereof. The methodmay comprise administering intranasally to the patient, atherapeutically effective amount of a substantially selectivekappa-opioid-receptor agonist in a pharmaceutically acceptablepreparation. In various embodiments, the kappa-opioid-receptor agonistmay be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A)receptors, such that it produces substantially no manic effect. Invarious embodiments, the kappa-opioid-receptor agonist also has D2agonist activity and, in particular, partial D2 agonist activity. Incertain embodiments, the kappa-opioid-receptor agonist may be salvinorinA. Administration may be with an intranasal delivery device.

In various embodiments, the affective disorder may be depression,bipolar disorder or anxiety disorder.

In various aspects of this embodiment, the kappa-opioid-receptor agonistmay be administered with either or both of a cannabinoid compound andketamine in a pharmaceutically acceptable preparation. Thepharmaceutically acceptable preparation for the cannabinoid compoundand/or ketamine may include the same carrier system in which thekappa-opioid-receptor agonist is administered and the substances may beadministered together or separately in any combination thereof.Alternatively, the carrier system for the cannabinoid compound and/orketamine may be different from that of the kappa-opioid-receptor agonistand the substances may be administered separately. In some embodiments,naltrexone is included.

In various embodiments, the present invention may involve a method oftreating addiction in a subject in need thereof. The method may compriseadministering intranasally to the patient, a therapeutically effectiveamount of a substantially selective kappa-opioid-receptor agonist in apharmaceutically acceptable preparation. In various embodiments, thekappa-opioid-receptor agonist may be devoid of activity on 5HT₂receptors, in particular 5HT_(2A) receptors, such that it producessubstantially no manic effect. In various embodiments, thekappa-opioid-receptor agonist also has D2 agonist activity and, inparticular, partial D2 agonist activity. In certain embodiments, thekappa-opioid-receptor agonist may be salvinorin A. Administration may bewith an intranasal delivery device.

In various embodiments, the addiction may be an addiction to nicotine,cocaine, opioids, amphetamine, methamphetamine, ethanol, heroin,morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well asother addictive substances and addictive behaviors.

In various aspects of this embodiment, the kappa-opioid-receptor agonistmay be administered with either or both of a cannabinoid compound andketamine in a pharmaceutically acceptable preparation. Thepharmaceutically acceptable preparation for the cannabinoid compoundand/or ketamine may include the same carrier system in which thekappa-opioid-receptor agonist is administered and the substances may beadministered together or separately in any combination thereof.Alternatively, the carrier system for the cannabinoid compound and/orketamine may be different from that of the kappa-opioid-receptor agonistand the substances may be administered separately. In some embodiments,naltrexone is included.

In yet another embodiment, the present invention may involve anintranasal delivery system. The system may comprise an intranasaldelivery device and a therapeutically effective amount of asubstantially selective kappa-opioid-receptor agonist in apharmaceutically acceptable preparation. In various embodiments, thekappa-opioid-receptor agonist may be devoid of activity on 5HT₂receptors, in particular 5HT_(2A) receptors, such that it does notproduce mania. In various embodiments, the kappa-opioid-receptor agonistalso has D2 agonist activity and, in particular, partial D2 agonistactivity. In certain embodiments, the kappa-opioid-receptor agonist maybe salvinorin A.

In various aspects of this embodiment, the system may include, inaddition to the kappa-opioid-receptor agonist, either or both of acannabinoid compound and ketamine in a pharmaceutically acceptablepreparation. The pharmaceutically acceptable preparation for thecannabinoid compound and/or ketamine may include the same carrier systemin which the kappa-opioid-receptor agonist is administered and thesubstances may be administered together or separately in any combinationthereof. Alternatively, the carrier system for the cannabinoid compoundand/or ketamine may be different from that of the kappa-opioid-receptoragonist and the substances may be administered separately. In someembodiments, naltrexone is included.

In various other embodiments, the present invention may involve aninhalation delivery system. The system may comprise an inhalationdelivery device and a therapeutically effective amount of asubstantially selective kappa-opioid-receptor agonist in apharmaceutically acceptable preparation. In various embodiments, thekappa-opioid-receptor agonist may be devoid of activity on 5HT₂receptors, in particular 5HT_(2A) receptors, such that it producessubstantially no manic effect. In various embodiments, thekappa-opioid-receptor agonist also has D2 agonist activity and, inparticular, partial D2 agonist activity. In certain embodiments, thekappa-opioid-receptor agonist may be salvinorin A.

In various aspects of this embodiment, the system may include, inaddition to the kappa-opioid-receptor agonist, either or both of acannabinoid and ketamine in a pharmaceutically acceptable preparation.The pharmaceutically acceptable preparation for the cannabinoid compoundand/or ketamine may include the same carrier system in which thekappa-opioid-receptor agonist is administered and the substances may beadministered together or separately in any combination thereof.Alternatively, the carrier system for the cannabinoid compound and/orketamine may be different from that of the kappa-opioid-receptor agonistand the substances may be administered separately. In some embodiments,naltrexone is included.

In various other embodiments, the present invention involves a method oftreating an affective disorder in a patient in need thereof. The methodmay comprise administering transdermally to the patient, atherapeutically effective amount of a substantially selectivekappa-opioid-receptor agonist in a pharmaceutically acceptablepreparation. In various embodiments, the kappa-opioid-receptor agonistmay be devoid of activity on 5HT₂ receptors, in particular 5HT_(2A)receptors, such that it produces substantially no manic effect. Invarious embodiments, the kappa-opioid-receptor agonist also has D2agonist activity and, in particular, partial D2 agonist activity. Incertain embodiments, the kappa-opioid-receptor agonist may be salvinorinA. Administration may be with a transdermal delivery device or system.

In various embodiments, the affective disorder may be depression,bipolar disorder or anxiety disorder.

In various aspects of this embodiment, the kappa-opioid-receptor agonistmay be administered with either or both of a cannabinoid compound andketamine in a pharmaceutically acceptable preparation. Thepharmaceutically acceptable preparation for the cannabinoid compoundand/or ketamine may include the same carrier system in which thekappa-opioid-receptor agonist is administered and the substances may beadministered together or separately in any combination thereof.Alternatively, the carrier system for the cannabinoid compound and/orketamine may be different from that of the kappa-opioid-receptor agonistand the substances may be administered separately. In some embodiments,naltrexone is included.

In various embodiments, the present invention may involve a method oftreating addiction in a subject in need thereof. The method may compriseadministering transdermally to the patient, a therapeutically effectiveamount of a substantially selective kappa-opioid-receptor agonist in apharmaceutically acceptable preparation. In various embodiments, thekappa-opioid-receptor agonist may be devoid of activity on 5HT₂receptors, in particular 5HT_(2A) receptors, such that it producessubstantially no manic effect. In various embodiments, thekappa-opioid-receptor agonist also has D2 agonist activity and, inparticular, partial D2 agonist activity. In certain embodiments, thekappa-opioid-receptor agonist may be salvinorin A. Administration may bewith a transdermal delivery device or system.

In various embodiments, the addiction may be an addiction to nicotine,cocaine, opioids, amphetamine, methamphetamine, ethanol, heroin,morphine, phencyclidine, 3,4-methylenedioxy-methamphetamine, as well asother addictive substances and addictive behaviors.

In various aspects of this embodiment, the kappa-opioid-receptor agonistmay be administered with either or both of a cannabinoid compound andketamine in a pharmaceutically acceptable preparation. Thepharmaceutically acceptable preparation for the cannabinoid compoundand/or ketamine may include the same carrier system in which thekappa-opioid-receptor agonist is administered and the substances may beadministered together or separately in any combination thereof.Alternatively, the carrier system for the cannabinoid compound and/orketamine may be different from that of the kappa-opioid-receptor agonistand the substances may be administered separately. In some embodiments,naltrexone is included.

In yet another embodiment, the present invention may involve atransdermal delivery system. The system may comprise a transdermaldelivery device and a therapeutically effective amount of asubstantially selective kappa-opioid-receptor agonist in apharmaceutically acceptable preparation. In various embodiments, thekappa-opioid-receptor agonist may be devoid of activity on 5HT₂receptors, in particular 5HT_(2A) receptors, such that it does notproduce mania. In various embodiments, the kappa-opioid-receptor agonistalso has D2 agonist activity and, in particular, partial D2 agonistactivity. In certain embodiments, the kappa-opioid-receptor agonist maybe salvinorin A.

In various aspects of this embodiment, the system may include, inaddition to the kappa-opioid-receptor agonist, either or both of acannabinoid compound and Ketamine in a pharmaceutically acceptablepreparation. The pharmaceutically acceptable preparation for thecannabinoid compound and/or ketamine may include the same carrier systemin which the kappa-opioid-receptor agonist is administered and thesubstances may be administered together or separately in any combinationthereof. Alternatively, the carrier system for the cannabinoid compoundand/or ketamine may be different from that of the kappa-opioid-receptoragonist and the substances may be administered separately. In someembodiments, naltrexone is included.

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves the treatment of neuropsychiatricconditions and disorders by administration of a substantially selectivekappa-opioid-receptor agonist in a pharmaceutically acceptablepreparation. Administration may be intranasal, transdermal or byinhalation. The substantially selective kappa-opioid-receptor agonistsinclude, in particular, salvinorin A as well as derivatives ofsalvinorin A (see for example U.S. Pat. No. 7,687,538, which isincorporated by reference).

As used herein, the following terms are defined with the followingmeanings, unless explicitly stated otherwise. Salvia is the genus namefor annual, biennial, or perennial herbs in the mint family. Salviadivinorum is a species containing psychoactive compounds, of which thediterpenoid compound, salvinorin A, is the principal component.Salvinorin A is a selective kappa-opioid-receptor agonist (Roth et al.,2004) and D2 receptor partial agonist (Seeman et al., 2009) with nosubstantial effect on 5-HTP_(2A) receptors (Roth et al., 2004).

Cannabis is the genus name for the annual, dioecious flowering herb inwhich psychoactive constituents, principally tetrahydrocannabinol (THC),occur in the floral calyces. Cannabis plants include Cannabis sativa,Cannabis indica, and Cannabis ruderalis as well as various crosses andhybrids. There are also known strains of Cannabis including “drug”strains which contain high levels of THC and low levels cannabidiol(CBD) and “non-drug” strains such as hemp which contain high levels ofCBD and low levels of THC.

The term “cannabinoid compound” as used herein, is intended to refer toterpenophenolic compounds that act on cannabinoid CB₁ and/or CB₂receptors in cells including phytocannabinoids, endocannabinoids andsynthetic cannabinoids. Phytocannabinoids can be found in Cannabisplants, endocannabinoids are produced naturally in the body andsynthetic cannabinoids are man-made.

Examples of phytocannabinoids include cannabigerol (CBG),cannabichromene (CBC), cannabidiol (CBD), tetrahydrocannabinol (THC),cannabinol (CBN), cannabielsoin (CBE), iso-tetrahydrocannabinol(iso-THC), cannabicyclol (CBL) and cannabicitran (CBT).

The endocannabinoids bind to central (CB₁) and peripheral (CB₂)cannabinoid receptors. Examples of endocannabinoids includearachidonoylethanolamine (anandamide), 2-arachidonoylglycerol,2-arachidonyl glyceryl ether, N-arachidonoyl dopamine andlysophosphatidylinositol.

Numerous synthetic cannabinoids have been made some of which have beenused medicinally, for example, nabilone and rimonabant.

The term “cannabinoid compound” can also refer to any individualcannabinoid or combination of cannabinoid compounds such as thenon-limiting example of THC+CBD+CBN or any other combination.

The term “about” when used before a numerical designation, e.g., pH,temperature, amount, concentration, and molecular weight, includingrange, indicates approximations which may vary by (+) or (−) 5%, 1% or0.1%.

As used in the specification and claims, the singular form “a”, “an” and“the” include plural references unless the context clearly dictatesotherwise. For example, the term “a pharmaceutically acceptable carrier”may include a plurality of pharmaceutically acceptable carriers,including mixtures thereof.

The term “and/or” is intended to mean either or both of two componentsof the invention.

The term “subject,” “individual” or “patient” is used interchangeablyherein, and refers to a human.

The term “agonist,” as used herein, refers to a moiety that interactswith and activates a receptor, and thereby initiates a physiological orpharmacological response characteristic of that receptor. The term“antagonist,” as used herein, refers to a moiety that competitivelybinds to a receptor at the same site as an agonist (for example, theendogenous ligand), but which does not activate the intracellularresponse initiated by the active form of the receptor and can therebyinhibit the intracellular responses by an agonist or partial agonist. Anantagonist does not diminish the baseline intracellular response in theabsence of an agonist or partial agonist. The term “inverse agonist”refers to a moiety that binds to the endogenous form of the receptor orto the constitutively activated form of the receptor and which inhibitsthe baseline intracellular response initiated by the active form of thereceptor below the normal base level of activity which is observed inthe absence of an agonist or partial agonist.

The term “device,” as used herein, refers to an apparatus or systemcapable of delivering a drug to patient in need thereof.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably and refer to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner, that apatient will benefit from treatment.

The term “nostril,” as used herein, is synonymous with “naris.”

The term “nasal delivery”, “intranasal delivery”, “nasal administration”or “intranasal administration” refers to a route of administrationwherein the pharmaceutical dosage form is taken to, or through, the nose(e.g., nasal cavity). Similarly, a “nasal delivery device” or an“intranasal delivery device” is intended to mean an apparatus thatadministers a drug into the nasal cavity. Non-limiting examples ofintranasal administration include introduction of a solution orsuspension in the form of a nasal spray or drops (direct instillation)or intranasal application of gel, emulsion or ointment.

The term “inhalation delivery” or “inhalation administration” refers toa route of administration wherein the pharmaceutical dosage form istaken into the airways and lungs by inhaling a gaseous, vaporized, oraerosolized drug preparation. Similarly, an “inhalation delivery device”is intended to mean an apparatus that administers a drug into theairways and lungs. The drug preparation may aerosolized using, e.g. anebulizer.

The term “transdermal delivery” refers to a route of administration inwhich the pharmaceutical dosage form is taken up through the skin.Similarly, a “transdermal delivery device” is intended to mean anyapparatus or system that administers a drug to be taken up through theskin.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent of a pharmaceutical composition that is compatible with theother ingredients of the formulation and not overly deleterious to therecipient thereof.

The term “carrier” refers to a diluent, adjuvant, excipient, or vehiclewith which the therapeutic is administered and includes, but is notlimited to such liquids and powders that are hydrophilic substances,hydrophobic substances and substances that possess both hydrophilic andhydrophobic properties such as emulsifiers.

By the term “substantially selective kappa-opioid-receptor agonist” itis meant that the agent has an affinity for kappa-opioid receptorsand/or kappa-opioid biological activity, for example EC₅₀ (concentrationof compound that gives half-maximal response) of at least 10-fold, atleast 100-fold, at least 1000-fold or greater than that for mu- anddelta-opioid receptors (see for example, Cunningham, 2011).

The term “substantially no effect on 5HT₂ receptors” and, in particular“substantially no effect on 5HT_(2A) receptors” is intended to mean acompound has receptor affinity and/or elicits receptor mediatedbiological activity that is less than 0.1, less than 0.01, less than0.001 or lesser than that for the kappa-opioid receptor (see for exampleRoth, 2004). Similarly, the term “produces substantially no maniceffect” it is meant that the compound does not produce a meaningfullysignificant manic effect in a population of subjects.

The term “therapeutically effective amount,” as used herein, refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, or individual thatis being sought by a researcher, healthcare provider or individual.

Intranasal delivery devices are known in the art. Thus, any devicesuitable for delivery of drug to nasal mucosa may be used. Non-limitingexamples of devices useful for the administration of liquid compositionsinclude vapor devices (e.g., vapor inhalers), drop devices (e.g.,catheters, single-dose droppers, multi-dose droppers, and unit-dosepipettes), mechanical spray pump devices (e.g., squeeze bottles,multi-dose metered-dose spray pumps, and single/duo-dose spray pumps),bi-directional spray pumps (e.g., breath-actuated nasal deliverydevices), gas-driven spray systems/atomizers (e.g., single- ormulti-dose HFA or nitrogen propellant-driven metered-dose inhalers,including traditional and circumferential velocity inhalers), andelectrically powered nebulizers/atomizers (e.g., pulsation membranenebulizers, vibrating mechanical nebulizers, and hand-held mechanicalnebulizers). Non-limiting examples of devices useful for theadministration of powder compositions (e.g., lyophilized or otherwisedried pooled compositions) include mechanical powder sprayers (e.g.,hand-actuated capsule-based powder spray devices and hand-actuatedpowder spray devices, hand actuated gel delivery devices),breath-actuated inhalers (e.g., single- or multi-dose nasal inhalers andcapsule-based single- or multi-dose nasal inhalers), and insufflators(e.g., breath-actuated nasal delivery devices).

Inhalation delivery devices are known in the art. Thus, any devicesuitable for delivery of drug to the lungs may be used. Non-limitingexamples of suitable inhalation devices for inhalation include varioustypes of modern inhalers based on different aerosolization technologies.For example, a metered-dose inhaler, a dry powder inhaler, a soft mistinhaler, or a nebulizer may be used. Metered-dose inhalers are typicallypressurized, i.e. the active ingredient and optional inactiveconstituents are dispersed or dissolved in a liquid, pressurizedpropellant. A metered-dose inhaler typically comprises a canister whichmay be made of plastic, glass, aluminum, stainless steel, or any othersuitable material; a metering valve allowing a metered quantity of theformulation to be dispensed with each actuation; and an actuator whichis often combined with a mouthpiece to allow the subject to operate thedevice and direct the aerosol into the patient's lungs via the mouth.

Transdermal delivery devices are known in the art. Thus, any devicesuitable for delivery of drug across the skin of a patient may be used.Devices known in the art include reservoir type devices involvingmembranes that control the rate of drug release to the skin and deviceswhere the drug is dispersed or dissolved in a matrix such as a pressuresensitive adhesive. Transdermal delivery devices may be made in the formof an article such as a tape, a patch, a sheet, a dressing or any otherform known to those skilled in the art. Generally, the device may in theform of a patch of a size suitable to deliver a preselected amount ofdrug through the skin. Generally, the device will have a surface area ofabout 5 cm² to about 100 cm² and, in particular, about 10 cm² to about40 cm².

Transdermal drug delivery devices typically involve a carrier (such as aliquid, gel, or solid matrix, or a pressure sensitive adhesive) intowhich a compound of the invention is incorporated.

For inhalation, or intranasal administration the preparation may containa compound of the invention in a liquid carrier for aerosol application.In various embodiments, the composition may be in the form of an aqueousor non-aqueous solution, suspension, liposomal dispersion, emulsion,microemulsion or a combination thereof. The carrier can containadditives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, mucoadhesives and/or preservatives such as parabens.

Methods well known in the art for making formulations may be found, forexample, in Remington, 2000. Further, methods for formulating compoundsfor intranasal and transdermal administration, including for extendingthe presence in in the nasal cavity, creating various emulsions,combining with cyclodextrins and other agents to enhance solubility,creating prodrugs, analogs, and increasing bioavailability, etc. arewell known. See, e.g., Bitter et al., 2011; Pastore et al., 2014.

The compounds of the present invention may be used for the treatment ofneuropsychiatric disorders including affective disorders such asdepression, bipolar disorder or anxiety disorder. Thus, the compoundsmay be used to treat abnormalities of mood or emotion includingdepression, bipolar disorder, dysthymia, post-traumatic stress disorder,schizoaffective disorder, schizophrenia and other psychotic disorders,anxiety disorders, panic disorder, traumatic stress disorders, phobicdisorders, and personality disorders with abnormal mood, such asborderline personality disorder, schizoid and schizotypal disorders andsuicide ideation.

The compounds of the present invention may also be used for treatingaddiction. Such addictions may be addiction to drugs, non-limitingexamples of which may include nicotine, alcohol, cocaine, opioids,amphetamine, methamphetamine, heroin, morphine, phencyclidine,3,4-methylenedioxy-methamphetamine, as well as other addictivesubstances. Additions may also include addictive behaviors, non-limitingexamples of which may include eating, gambling, sex, pornography,videogames, work, exercise, spiritual obsession, self-harm, travel andshopping addiction.

Salvinorin A may be administered as Salvia divinorin or in a purifiedform of salvinorin A. When Salvia divinorin is administered, the dose iscalculated in terms of the amount of salvinorin A administered from thepreparation. The dose of salvinorin A when administered by inhalationmay be in a range of from as low as about 50 μg, about 75 μg, about 100μg, about 250 μg or about 400 μg up to about 500 μg, about 1000 μg,about 2000 μg, about 5000 μg or about 10,000 μg. The dose of salvinorinA when administered intranasally may be in a range of from as low asabout 5 μg, about 7.5 μg, about 10 μg, about 25 μg or about 50 μg orabout 100 μg up to about 200 μg, about 500 μg, about 1000 μg, about 2000μg, about 5000 μg or about 10,000 μg.

The dose of salvinorin A when administered transdermally may be in arange of from as low as about 5 μg, about 7.5 μg, about 10 μg, about 25μg or about 50 μg or about 100 μg up to about 200 μg, about 500 μg,about 1000 μg, about 2000 μg, about 5000 μg or about 10,000 μg.

Ketamine may be administered intranasally as the hydrochloride at a dosein a range of from as low as about 5 μg, about 10 μg, about 20 μg, about30 μg up to about 75 μg, about 125 μg, about 200 μg, or about 300 μg. Insome embodiments, naltrexone is also administered to potentiate theeffects of the ketamine administraion.

The cannabinoid compound may be administered by combustion andinhalation of the floral calyces of a Cannabis plant or in a purifiedform of the cannabinoid compound. When Cannabis plant is administered,the dose is calculated in terms of the amount of the cannabinoidcompound administered from the preparation. The dose of the cannabinoidcompound when administered by inhalation may be in a range of from aslow as about 200 μg, about 500 μg, about 1000 μg, about 2000 μg or about5 μg up to about 10,000 μg, about 15,000 μg, about 20,000 μg, about25,000 μg, about 50,000 μg, about 75,000 μg, about 100,000 μg, about150,000 μg, or about 250,000 μg, or about 500,000 μg or about 750,000μg, or about 1,000,000 μg, or about 1,500,000 μg or about 2,000,000 μg,or about 2,500,000 μg, or about 3,000,000 μg, or about 3,500,000 μg, orabout 4,000,000 μg, or about 4,500,000 μg, or about 5,000,000 μg.

Administration may be once a day (q.d.), twice a day (b.i.d.), threetimes a day (t.i.d.), four times a day (q.i.d.) or at more or lessfrequent intervals such as once every other day (q.a.d.), once everythird day, twice a week (bis in 7 d.), once a week (QWK), once everyother week, etc. Alternatively, administration may be as needed(p.r.n.).

Preferred embodiments are described in the following examples. Otherembodiments within the scope of the claims herein will be apparent toone skilled in the art from consideration of the specification orpractice of the invention as disclosed herein. It is intended that thespecification, together with the examples, be considered exemplary only,with the scope and spirit of the invention being indicated by theclaims, which follow the examples.

EXAMPLE 1 Salvinorin A administration is Anxiolytic, Antidepressant andMotivationally Stimulating with No Manic Side Effects

The effects of salvinorin A were evaluated in one subject with bipolardisorder following Salvia divinorum administration by combustion andinhalation at a dose of approximately 8 mg of enhanced leaf of ‘regularstrength’ from a known online source (sagewisdom.com). After a brief,2-5 minute period of mild hallucinations accompanied by euphoria, thesubject experienced anxiolytic, antidepressant and motivationallystimulating effects for a period of 24 hours or greater with no manicside effects. It is noteworthy that this subject had experienced maniaeven on very small, sub-therapeutic doses of traditional antidepressantsincluding celexa and sertraline—serotonin agonists and partial agonists.A slight tremor appeared shortly after administration, however,co-administration of Cannabis by combustion and inhalation along withthe Salvia divinorum eliminated the tremor. This method was repeatedapproximately 20 times with consistent results.

Co-administration of Cannabis by combustion and inhalation and/orketamine (ketamine hydrochloride, at varying doses, generally about 30to about 75 mg) by intranasal administration along with Salvia divinorumby combustion and inhalation appeared to potentiate the anxiolytic andantidepressant effects of Salvia divinorum alone.

The subject also takes clonazepam, orally and/or sublingually, and hasreported that clonazepam (at varying doses, generally about 1.5 mg,b.i.d. and occasionally, about 0.5 mg up to about 2.5 mg p.r.n.), alongwith co-administration of Cannabis by combustion and inhalation and/orketamine by intranasal administration with Salvia divinorum bycombustion and inhalation appeared to potentiate the anxiolytic andantidepressant effects of the Salvia divinorum alone and helped tofurther alleviate any anxiety, tremor or any other side effect before,during or after administration of the Salvia divinorum.

EXAMPLE 2 Effects of Intranasal or Transdermal Administration ofSalvinorin A on Behavioral Activity

Preparation of the intranasal and transdermal salvinorin A is by knownmethods. See, e.g., Bitter et al., 2011; Pastore et al., 2015.

Following intranasal or transdermal delivery of salvinorin A at 3separate dosages, with a negative control administered vehicle only,rats are monitored for a total of 40 minutes by an experimenter who isblinded to condition. Signs of altered behavior, including staring,immobility, increased or decreased response to stimuli (e.g. tactile,auditory), and changes in locomotor patterns are recorded.

For each method of administration, a total of 48 Sprague-Dawley male &female CD rats ˜45 days old are utilized (Table 1).

TABLE 1 Summary of Treatment Groups Number Group Treatment Purpose ♂ ♀T-1 Concentration 1 Test Article (Dose 1) 6 6 T-2 Concentration 2 TestArticle (Dose 2) 6 6 T-3 Concentration 3 Test Article (Dose 3) 6 6 C-1Vehicle only Negative Control 6 6

Following a 5-7 day acclimation phase, rats are randomly divided into 4groups (C1, T1, T2, T3; Table 1) and receive intranasal or transdermaladministration of the appropriate dosage of Compound X.

Visual (real-time) monitoring is performed for 10 minutespre-administration and 30 minutes post-administration of the compound.

Animals are observed in real time to assess behavioral anomalies, with 4animals monitored simultaneously (1 from each condition). Periods ofstaring, increased or decreased response to stimuli (e.g. tactile,auditory), and any other unusual behaviors are noted. Animals are alsovideo recorded, with locomotor activity, rearing, grooming, and periodsof immobility assessed using the AnyMaze™ behavioral scoring system(Stoelting Co., Wood Dale Ill. 60191 US). All behavioral evaluations areperformed by an experimenter blinded to condition. The following 2phases are used to allow for within and between animal comparisons:

Parametric data is evaluated using 2-way ANOVA (SEX by TREATMENT).Statistically significant main effects are further investigated usingTukey's post hoc analysis. Non-parametric analyses are assessed using aKruskal-Wallis test with Dunn-Bonferroni pairwise comparisons for posthoc analysis. Significance level for all tests is p≤0.05.

EXAMPLE 3 Effects of Intranasal or Transdermal Administration ofSalvinorin A on Anxiety

Salvinorin A is administered intranasally or transdermally to rats atone of 3 different dose levels (1, 2 or 3). In addition to a normalcontrol, there is both a positive and a negative control group. For thepositive control, rats receive a 5 mg/kg injection (i.p.) oftracazolate, a non-benzodiazepine anxiolytic compound (Thompson et al.,2002). As a negative control, FG7142 (5 mg/kg i.p.) is administered toproduce anxiogenic behavior (Pellow and File, 1986). The normal controlgroup receives an i.p. injection of an equivalent volume (2 ml/kg) ofsterile saline. All control groups also receive an equivalent volume ofvehicle delivered in an identical manner to that used for the testarticle (i.e. intranasal or transdermal administration).

A total of 60 Sprague-Dawley male CD rats ˜45 days old are utilized foreach administration method (Table 2).

TABLE 2 Summary of Treatment Groups Group Treatment Purpose Number T-1Concentration 1 Test Article (Dose 1) 10 T-2 Concentration 2 TestArticle (Dose 2) 10 T-3 Concentration 3 Test Article (Dose 3) 10 VehVehicle Normal Control 10 Pos Tracazolate Anxiolytic 10 Neg FG7142Anxiogenic 10

Following a minimum 7 day acclimation phase, rats are randomly dividedinto 6 groups (T1, T2, T3, Veh, Pos, Neg; Table 2).

Forty-five minutes prior to behavioral testing, an i.p. injection isadministered to all animals in a volume of 2 ml/kg as follows: rats inthe anxiolytic control group, receive tracazolate (5 mg/kg), apyrazolopyridine that reduces anxiety-like behaviors in rodents (Pellowand File, 1986), an effect believed to result from allosteric modulationof extrasynaptic GABA_(A) receptor function (Thompson et al., 2002;Belelli et al., 2009). As an anxiogenic control, a second group of ratsreceive FG7142 (N-methyl-β-carboline-3-carboxamide), a beta-carbolinethat acts as a partial inverse agonist at the benzodiazepine allostericsite (Evans and Lowry, 2007) and produces demonstrated increases inanxiety-like behaviors in various tasks (Thompson et al., 2002; Arrantet al., 2013). Rats in experimental groups (i.e. those who have receiveda test compound), as well as rats in the normal control group receive aninjection of sterile saline.

Thirty minutes prior to behavioral testing, rats in test article groupsreceive intranasal or transdermal administration of salvinorin A at oneof the 3 dosage levels. Animals in the normal control group receiveadministration of vehicle only in a volume equivalent to that utilizedfor the experimental animals. Following treatment as per its assignedgroup, each rat is tested in either the Open Field (OF) test or theElevated Plus Maze (EPM) to assess anxiety-like behaviors. One weeklater, the same rats receive the same group treatment (experimental orcontrol) and undergo testing in the paradigm not yet experienced (i.e.OF or EPM). All tests are video recorded for scoring and documentationpurposes.

Ultrasonic vocalizations (USVs) is also recorded and analyzed to providean additional level of anxiety-related measures.

The following behavioral tests are performed:

Elevated Plus test (Bailey and Crawley, 2009)—The arena for this testconsists of four aims, two with sidewalk, and two open (a “plus”configuration), thus providing a measure of anxiety associated with openspace, unprotected regions. The maze is elevated ˜2 feet above thefloor. Rats are started in the center (neutral) zone of the test, andbehavioral measures include latency to enter and percent of time spentin the closed arms as recorded during a 10 minute trial.

Open Field test (Gould et al., 2009)—The open field test allowsassessment of activity levels, locomotion, and anxiety-relatedbehaviors. Rats are started in the center of the arena (˜4.5 footdiameter), and measures during a 10 minute test period may include:latency to reach the outer wall region, time spent in thigmotaxicbehavior, number of entries into and time spent in the center region,distance travelled, average speed in each region, number and time spentrearing, number and time spent grooming, and comparison of activitiesduring the first and last minute, and first and last half of the task.

Ultrasonic Vocalizations—Ultrasonic vocalization emissions are recordedduring testing, with number, duration, and frequency range of callsassessed to provide an additional measure of affective state duringtesting. See also Bourin, 2015; and Campos et al., 2013.

EXAMPLE 4 Antidepressant Effects of Intranasal or TransdermalAdministration of Salvinorin A

For confirming its antidepressant effects, salvinorin A is administeredintranasally or transdermally to rats at one of 3 different dose levels(1, 2 or 3), with a control group that receives an equivalent volume ofvehicle delivered in an identical fashion to the test article.

A total of 40 Sprague-Dawley male CD rats ˜45 days old are utilized foreach administration method (Table 3).

TABLE 3 Summary of Treatment Groups Group Treatment Purpose Number T-1Concentration 1 Test Article (Dose 1) 10 T-2 Concentration 2 TestArticle (Dose 2) 10 T-3 Concentration 3 Test Article (Dose 3) 10 VehVehicle Normal Control 10

Following the acclimation phase, rats are randomly divided into 4 groups(T1, T2, T3, Veh; Table 3).

On the day of the test phase, ultrasonic vocalization (USV) emissionsare recorded from each rat at 3 time points—prior to compoundadministration, immediately following compound administration, andimmediately after the test phase. Thirty minutes prior to the testphase, rats in experimental groups receive intranasal or transdermaladministration of the appropriate dosage of salvinorin A (T-1, T-2, orT-3). Rats in control groups receive an equivalent volume of vehicledelivered in an identical manner.

Following treatment as per its assigned group, each rat is tested in theForced Swim Test (FST) to assess depressive behaviors. All tests arevideo recorded for scoring and documentation purposes.

The forced swim test is based on a rodent's aversion to water, andsubsequent desire to try and escape when submerged. To induce the model,rats are placed in an inescapable water-filled container (˜8″diameter×20″ deep) for 15 minutes (pre-test phase). Duration ofstruggling/climbing, immobility, and swimming activities are measuredduring each 5 minute block to provide a baseline evaluation. Twenty-fourhours later, rats are once again placed in an inescapable water-filledcontainer, and measures are recorded for 5 minutes (test phase).

To provide an additional level of affective state, USV emissions arerecorded for 5 minutes prior to, and following, the pre-test phase. Inaddition, USVs will be recorded on the testing day for 5 minutes priorto the test phase, 5 minutes immediately following compoundadministration, and 5 minutes following the test phase.

Parametric data is evaluated using ANOVA, with repeated measuresutilized where appropriate. Statistically significant main effects arefurther investigated using Tukey's post hoc analysis. Non-parametricanalyses will be assessed using a Kruskal-Wallis test withDunn-Bonferroni pairwise comparisons for post hoc analysis. The Friedmantest will be used to evaluate non-parametric repeated measures data.Significance level for all tests will be p≤0.05.

See also Bogdanova et al., 2013; Krishnan and Nestler, 2011; Abelaira etal., 2013; Gould and Einat, 2007; and Abulseoud et al., 2014.

EXAMPLE 5 Effects of Intranasal or Transdermal Administration ofSalvinorin A on Chronic Depression

Chronic exposure to mild, unpredictable stress is used as a rodent modelof long-term depression. This paradigm results in decreased consumptionof sweetened water, a treat that is generally rewarding to rats.

For confirming its effects on chronic depression, salvinorin A isadministered intranasally or transdermally to rats at one of 3 differentdose levels (1, 2 or 3), with a control group that receives anequivalent volume of vehicle delivered in an identical fashion to thetest article.

A total of 60 male Wistar CD rats ˜45 days old are utilized for eachadministration method (Table 4).

TABLE 4 Summary of Treatment Groups Group Treatment Stress PurposeNumber A Compound X1 Yes Test Article Dose 1 12 B Compound X2 Yes TestArticle Dose 2 12 C Compound X3 Yes Test Article Dose 3 12 D Vehicle YesNegative Control 12 E Vehicle No Normal Control 12

Starting 24 hours after arrival in the facility, rats will be acclimatedto a sugar water solution (1% sucrose), to avoid neophobic behaviorsduring the testing period. Baseline measures of sucrose preference willbe obtained prior to model induction.

Upon study initiation, rats are randomly divided into 5 groups (X1, X2,X3, Negative Control, Normal Control; Table 4).

Chronic mild stress protocols are performed for a 6 week period asoutlined below, with a 24 hour sucrose preference test administeredweekly.

For the final 3 weeks of the chronic mild stress protocol, each ratreceives daily salvinorin

A administration as per its assigned group. Control (non-stressed) ratsreceive an equivalent volume of vehicle, delivered in an identicalfashion as the test article. As during the induction phase, a 24 hoursucrose preference test is administered weekly.

To produce a model of chronic depression, a series of mild,unpredictable stressors will be utilized, with protocols adapted fromprevious literature (Harden et al., 2012; Lopez-Lopez et al., 2016; Pappet al., 1996). A decrease in consumption of a rewarding treat (sugarwater) over a 24 hour presentation period (tested once per week; seeBehavioral Testing section below) is considered indicative of depressedbehavior (anhedonia).

Stressors to be utilized include a 16 hour food deprivation period, 15hour water deprivation followed by 1 hour empty water bottlepresentation, 36 hours continuous light, 9 hours wet cage bedding, 15minute immersion in cold water, 5 hour foreign object presentation (someobjects will restrict movement in cage), 5 hours inclined (45° cage),and 3 hours noise (˜40dB) to be presented with or without otherstressors.

Prior to model induction, a baseline level for sucrose preference isestablished over a 24 hour period as outlined below.

Sucrose Preference Testing—Once per week, for a 24 hour period, regularwater bottles will be replaced with two pre-weighed bottles, onecontaining regular water, and one with a 1% sucrose solution (sugarwater). After 24 hours, bottles will be weighed again, and consumptionof each will be recorded. No stressors will be administered during orfor 12 hours prior to this time period.

Parametric data will be analyzed using ANOVA, with repeated measureswhere appropriate. Statistically significant main effects will befurther investigated using Tukey's post hoc analysis. Significance levelfor all tests will be p≤0.05.

See also Lynch et al., 2010 and Planeta, 2013.

EXAMPLE 6 Effects of Intranasal or Transdermal Administration ofSalvinorin A on Addictive Behaviors

Reinforcing effects of drugs of abuse are believed to play a key role insubstance abuse and addiction; paradigms that measure drug reinforcedbehaviors allow for evaluation of compounds that may interfere withthese processes. The conditioned place preference paradigm providesassessment of a drug's rewarding effects, and when used with a knownaddictive substance, the paradigm allows for screening of compounds withpotentially therapeutic benefits.

For confirming its effects on addictive behaviors, salvinorin A isadministered intranasally or transdermally to rats at one of 3 differentdose levels (1, 2 or 3), with a control group that receives anequivalent volume of vehicle delivered in an identical fashion to thetest article.

Control groups are saline only exposure (negative control) or cocaineonly exposure (positive control) plus administration of an equivalentvolume of vehicle delivered in an identical fashion to the test article(i.e. intranasal administration).

A total of 50 Sprague-Dawley male SD rats ˜45 days old upon arrival inthe facility will be utilized for each administration method (Table 5).

TABLE 5 Summary of Treatment Groups Group Treatment Purpose Number ACompound X1 Test Article Dose 1 10 B Compound X2 Test Article Dose 2 10C Compound X3 Test Article Dose 3 10 D Saline/vehicle Negative Control10 E Cocaine/vehicle Positive Control 10

Upon study initiation, rats are randomly divided into 5 groups (X1, X2,X3, Pos, Neg; Table 5). All phases of the study are performed underreverse light cycle.

One day prior to the habituation phase of the study, rats receive asingle intraperitoneal (i.p.) injection of saline prior to beingreturned to the home cage.

During habituation, rats are exposed to the testing apparatus for 15minutes per day for 3 days.

During the conditioning phase, each animal is administered theappropriate compound (cocaine or saline alternated over days) andimmediately be placed in the associated chamber (drug or vehicle asappropriate) of the apparatus for 30 minutes per day for 8 consecutivedays. Saline control animals receive saline only each day, with chamberpresentation alternated over days.

On the testing day, 24 hours after the last conditioning trial, each ratreceives intranasal or transdermal compound administration as per itsassigned group, and is tested at the post-administration time point asspecified by the sponsor to determine the effects of the various dosagelevels of the compound on cocaine-induced CPP. All tests are videorecorded for scoring and documentation purposes by experimenters blindedto rat condition.

An i.p. injection of either cocaine (20 mg/kg) or saline in a maximumvolume of 10 ml/kg will be administered to rats during conditioningtrials as specified in the behavioral testing section below.

The following behavioral tests are performed:

Cocaine-induced Conditioned Place Preference test (CPP)(Buccafusco,2009; Galaj et al. 2014)—This test provides an assessment of the degreeof reward associated with cocaine administration. The testing apparatusconsists of two compartment chambers plus a center “tunnel” area(unforced choice) separated by doors, with the two larger outer chambersvarying in both color (e.g. black vs white) and floor texture (e.g.horizontal grid vs cross-grid). The center connecting chamber has nospecial characteristics, is not paired with any compound and is notaccessible during habituation. Measures that are evaluated include timespent in each chamber, first chamber chosen, chamber entries, speed, anddistance travelled. There are three stages:

1) Habituation—rats are placed in the test apparatus and allowed freeaccess for 15 minutes per day for a total of 3 days to eliminate noveltyas a confounding variable. Time spent in each compartment is recorded todetermine compartment preference prior to conditioning.

In order to habituate rats to injections, an i.p. injection of saline isadministered one day prior to the first apparatus exposure. Followingthis injection, rats are placed back in their home cage.

2) Conditioning—rats are conditioned over 8 consecutive days, withcocaine administration repeated once every other day for a total of 4cocaine conditioning days. On cocaine conditioning days, rats are givenan injection of cocaine (20 mg/kg i.p.), and are immediately confinedfor 30 minutes in the compartment for which they showed the leastpreference during the habituation stage (biased procedure). On alternatedays, rats are given an injection of saline, and are confined to theopposite chamber to that utilized during cocaine conditioning. The orderof cocaine conditioning is counterbalanced across rats. One group ofrats (negative control) will receive a daily injection of vehicle onlyand alternately be exposed to each compartment.

3) Testing—24 hours following the last conditioning session, all ratsreceive intranasal administration of the appropriate test article doseor an equivalent volume of vehicle. Cocaine-induced CPP is assessed byplacing the rat in the center compartment and allowing free access tothe entire apparatus for 15 minutes. Time spent in each compartment ismeasured.

Parametric data will be analyzed using ANOVA. Statistically significantmain effects are further investigated using Tukey's post hoc analysis.Significance level for all tests will be p≤0.05.

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In view of the above, it will be seen that several objectives of theinvention are achieved and other advantages attained.

As various changes could be made in the above methods and compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

All references cited in this specification are hereby incorporated byreference. The discussion of the references herein is intended merely tosummarize the assertions made by the authors and no admission is madethat any reference constitutes prior art. Applicants reserve the rightto challenge the accuracy and pertinence of the cited references.

What is claimed is:
 1. A method of treating tremor caused byadministration of a substantially selective kappa-opioid-receptoragonist in a patient, the method comprising: administering ketamineand/or a cannabinoid in a pharmaceutically acceptable preparationsufficient to treat the tremor.
 2. The method of claim 1, wherein thesubstantially selective kappa-opioid-receptor agonist is salvinorin A.3. The method of claim 2, wherein the salvinorin A is administeredintranasally.
 4. The method of claim 2, wherein the salvinorin A isadministered transdermally.
 5. The method of claim 1, wherein thesalvinorin A is administered by combustion and inhalation.
 6. The methodof claim 1, wherein the patient has an affective disorder.
 7. The methodof claim 6, wherein the patient is treated with the substantiallyselective kappa-opioid-receptor agonist to treat the affective disorder.8. The method of claim 7, wherein the substantially selectivekappa-opioid-receptor agonist is salvinorin A.
 9. The method of claim 6,wherein the affective disorder is depression, bipolar disorder, anxietydisorder, or depression.
 10. The method of claim 1, wherein the patienthas an addiction.
 11. The method of claim 10, wherein the patient istreated with the substantially selective kappa-opioid-receptor agonistto treat the addiction.
 12. The method of claim 11, wherein thesubstantially selective kappa-opioid-receptor agonist is salvinorin A.13. The method of claim 10, wherein the addition is to an addictivebehavior selected from the group consisting of eating, gambling, sex,pornography, video games, work, exercise, spiritual obsession,self-harm, travel and shopping addiction.
 14. The method of claim 1,wherein ketamine is administered without a cannabinoid.
 15. The methodof claim 1, wherein a cannabinoid is administered without ketamine. 16.The method of claim 1, wherein both ketamine and a cannabinoid isadministered.
 17. The method of claim 1, wherein the cannabinoid isadministered by combustion and inhalation.
 18. The method of claim 1,wherein the cannabinoid is administered by inhalation of a vaporizedpreparation.
 19. The method of claim 1, wherein the ketamine isadministered intranasally.